Drug Eluting Balloon

ABSTRACT

The present invention is an inflatable balloon which is enclosed by an expandable cover which becomes increasingly porous/permeable during expansion. The balloon is coated or enclosed with a matrix which contains a pharmaceutically active agent. During expansion of the balloon, the pharmaceutically active agent is released or extruded through the expandable cover into a body cavity such as an artery or vein. The present invention also provides for a method of treating a disease or condition by delivering the inflatable balloon to a particular body cavity.

FIELD OF THE INVENTION

The present invention is an inflatable balloon which is enclosed by anexpandable cover which becomes increasingly porous/permeable duringexpansion. The balloon is coated or enclosed with a matrix whichcontains a pharmaceutically active agent. During expansion of theballoon, the pharmaceutically active agent is released or extrudedthrough the expandable cover (e.g., a membrane) into a body cavity suchas an artery or vein. The present invention also provides for a methodof delivering the inflatable balloon as well as the pharmaceuticallyactive agent to a body cavity.

BACKGROUND

Atherosclerosis involves a thickening of the arterial wall.Pathologically, atherosclerosis results from invasion and accumulationof white blood cells (also referred to as foam cells) and proliferationof intimal smooth muscle cell which forms a fibrofatty plaque in thearterial wall. Potentially, atherosclerosis can affect any arterialblood vessel, either centrally or peripherally, causing a narrowing oreven complete obstruction of any artery. Angioplasty is a therapeutictechnique involving mechanical widening of the obstructed artery.

Percutaneous coronary intervention (PCI), also known as coronaryangioplasty, is a therapeutic procedure used to treat the narrowed orstenotic section of the coronary artery of the heart due to coronarylesions or obstructions. A guide catheter may be used in PCI to providesupport and easier passage for another catheter or device(microcatheter, stents, balloons, etc.) to access the target site. Forexample, a guide catheter can be inserted through the aorta and into theostium of the coronary artery. The guide catheter is then inserted intothe opening or ostium of the artery to be treated and a guidewire orother instrument passed through the lumen of the guide catheter andinserted into the artery beyond the occlusion or stenosis. Peripherally,percutaneous transluminal intervention or PTA is used to treat narrowingor stenosis of arteries such as the iliac, femoral, popliteal, renal orcarotid arteries. Neurovascular angioplasty is also growing inimportance as a means for treating stroke.

In certain circumstances, a stent may be inserted into the blood vesselduring angioplasty in order to maintain patency of the lumen. However, aknown complication of stenting is restenosis, where the blood vesselnarrows as a result of the invasion of smooth muscle cells andaccumulation of the extracellular matrix in response to injury fromangioplasty. In order to prevent restenosis, stents may be coated with avariety of different, antiproliferative pharmacological agents such assirolimus (drug eluting stents). Although drug eluting stents haveproved very effective at treating occluded coronary arteries, thereremains a small, but measureable incidence of severe complications afterstent implantation resulting from stent thrombosis. Luscher et al.Circulation 115:1051 (2007). Stent thrombosis has a very mortality andmorbidity. Id.

Drug eluting balloons (DEB) offer an alternative to POBA (Plain OldAngioplasty Balloon), or bare or drug eluting stents. Importantly, DEBcan provide several distinct advantages when compared with these othermodes of intervention. Waksman et al. Circulation: CardiovascularInterventions 2:352 (2009). For example, drug eluting stents do not workwell with long tortuous vessels, small vessels (i.e., less then 2.5 mmin diameter) or in long, diffuse calcified lesions. Id. First generationDEB have been limited to the delivery of paclitaxel given the method andmechanics of drug transfer from the balloon surface to the vessel wall.Moreover, sustained release of paclitaxel is not required for a longlasting anti-proliferative effect. A drug eluting balloon allows forrapid delivery of a comparatively large quantity of drug over a shortperiod of time. Other advantages of a drug eluting balloon include, (a)homogenous drug transfer to the entire vessel wall; (b) rapid release ofhigh concentrations of the drug over periods no longer than a week; (c)absence of foreign body, i.e., stent, could decrease chronicinflammation and the trigger for late thrombosis; (d) absence of a stentallows the artery's original anatomy to remain intact, such as in casesof bifurcation or small vessels; and (e) with local drug delivery,dependence on antiplatelet therapy could be decreased. Id.

Thus, there is an on-going need to develop drug eluting balloons whichcan deliver drugs effectively to the vascular space or to any other bodycavity over a sustained period of time.

SUMMARY OF THE INVENTION

The present invention is an inflatable balloon which is enclosed by anexpandable cover which becomes increasingly porous or permeable duringexpansion. The balloon may comprise a coating. The coating may futhercomprise at least one pharmaceutical agent. The coating may be abiocompatible matrix. During expansion of the balloon, thepharmaceutically active agent is released through the expandable cover(e.g., a membrane) into a body cavity such as an artery or vein. Thepresent invention also provides for a method of treating a condition ordisease by delivering (or inserting) the inflatable balloon to a bodycavity with subsequent delivery of a pharmaceutically active agent tothe body cavity.

The inflatable balloon can be an angioplasty balloon which is positionedon a catheter or other flexible shaft device. The balloon is coated withat least one pharmaceutically active agent. The coating may be in theform of any biocompatible matrix. For example, the biocompatible matrixmay be a semisolid such as a gel, a tape, a tube, spiral-cut tube orother form of wrapping. The pharmaceutically active agent may besuspended, embedded or dissolved in a biocompatible matrix. Thepharmaceutically active agent may be miscible or immiscible with thebiocompatible matrix. In certain embodiments, the pharmaceuticallyactive agent may be encapsulated in one or more particles such as one ormore, microspheres, liposomes, nanoparticles (e.g., nanogels) or otherparticles such as, cyclodextran. The gel may be a hydrogel which can bedried and then re-hydrated prior to the expansion of the balloon in vivoor in vitro.

In certain embodiments, the balloon and the biocompatible matrix areenclosed by an expandable cover which conforms to the balloon. Theexpandable cover may be semi-permeable or porous when the balloon is inan unexpanded state. In other embodiments, the expandable cover issubstantially impermeable or non-porous when the balloon is in anunexpanded state.

When the balloon expands, permeability or porosity of the expandablecover to the external environment (e.g., plasma, blood, body fluid,etc.) increases. For example, during inflation of the balloon, theexpansion of the balloon stretches or radially expands the expandablecover. As the balloon expands, pores or channels may form or mayincrease in size and/or number in the expandable cover. In certainembodiments, when the coated balloon is initially exposed to an aqueousenvironment, e.g., plasma or phosphate buffered saline, for a definedperiod of time, fluid is able to penetrate the expandable cover andbegin to solubilize the biocompatible matrix. This initialsolubilization of the biocompatible facilitates expansion of the coating(fluidizes) as the expandable balloon is inflated. As the balloonexpands, plasma or other aqueous fluids, can continue to diffuse intothe annular space or lumen between the expandable cover and the balloon.Upon inflation, the coating continues to dissolve, releasing thepharmaceutically active agent through the expandable cover into the bodycavity, such as as the artery or vein. In one embodiment, the coating isinitially dehydrated. Once in contact with the plasma or other aqueousfluid, the coating is rehydrated and then dissolved. The rate of releaseof the pharmaceutically active agent is variable and is dependent on anumber of different factors, including the rehydration process andnature of the biocompatible matrix, the rate of extent of expansion ofthe balloon and the degree of porosity/permeability of the expandablecover.

The expandable cover may comprise a plurality of pores.

The permeability and/or porosity of the expandable cover in an expandedstate is greater than the permeability and/or porosity of the expandablecover when it is in an unexpanded state. The permeability and/orporosity of the expandable cover in the expanded state may be at least20% greater, at least 30% greater, at least 40% greater, at least 50%greater, at least 60% greater, at least 70% greater, at least 80%greater, at least 90% greater, at least 100% greater, at least 120%greater, at least 150% greater, at least 200% greater, at least 250%greater, at least 300% greater, or range from about 20% to about 400%greater, from about 50% to about 300% greater, or from about 100% toabout 200% greater, as compared with the permeability and/or porosity ofthe expandable cover in an unexpanded state.

In one embodiment, the coating is or comprises a biocompatible matrixsuch as a hydrogel.

The pharmaceutical agent can be encapsulated in a plurality ofmicrospheres, nanoparticles (e.g., nanogels), liposomes, or cyclodextranparticles in the biocompatible matrix. In certain embodiments, thenanoparticle is formed from a nanogel which may be formed fromN-isopropylacrylamide, N-vinyl pyrrolidone and pegylated maleic acid andcombinations thereof.

In another embodiment, the coating is a thin film which can be formedfrom hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose(CMC), hydroxypropyl cellulose (HPC), poly (vinyl pyrrolidone) (PVP),poly (vinyl alcohol) (PVA), poly (ethylene oxide) (PEO), pullulan,chitosan, sodium alginate, carrageenan or gelatin. The coating may be inthe form of a tape which can be wrapped around the balloon, e.g., in aspiral configuration.

In one embodiment, the expandable cover is formed from a polymer such asexpanded poly(tetrafluoroethylene) (ePTFE) or ultra-high molecularweight polyethylene.

In certain embodiments, the total surface load of the pharmaceuticallyactive agent in the coating on the balloon ranges from about 1 μg/mm² toabout 50 μg/mm².

When the balloon is in an unexpanded state, less than about 10% (w/w) ofthe pharmaceutically active agent is released from the inflatableballoon in an unexpanded state, when the inflatable balloon is incubatedfor about one hour at 37° C. in an aqueous solution. In certainembodiments, when the balloon is expanded, greater than about 50% (w/w),greater than about 60% (w/w), greater than about 70% (w/w), greater thanabout 80% (w/w), greater than about 90% (w/w), or greater than about 95%(w/w), of the pharmaceutically active agent is released from theinflatable balloon in an expanded state, when the inflatable balloon isincubated for one hour in an aqueous solution at 37° C. In certainembodiments, about 100% (w/w) of the pharmaceutically active agent isreleased from the inflatable balloon in an expanded state when theinflatable balloon is incubated for one hour in an aqueous solution at37° C. When the balloon is expanded, the diameters of the pores rangefrom about 1 μm to about 100 μm or about 20 μm to about 80 μm.

The pharmaceutically active agent may be an anti-proliferative agentsuch as paclitaxel, everolimus, tacrolimus, sirolimus, zotarolimus,biolimus and rapamycin or mixtures thereof. In one embodiment, theexpandable cover is tubular in shape.

The inflatable balloon may be used to treat a disease or a condition.The method may involve inserting the inflatable balloon into a bodycavity. The body cavity can be an artery such as a coronary,infrainguinal, aortoiliac, subclavian, mesenteric, basilar and renalartery. Alternatively, the body cavity can be a urethra, bladder,ureters, esophagus, stomach, colon, trachea, bronchi or alveoli.

In certain embodiments, the present disclosure provides for aninflatable balloon comprising at least one inflatable body portion andat least one pharmaceutically active agent. The inflatable body portionof the inflatable balloon is covered by a cover that is permeable tosaid pharmaceutically active agent at least when said inflatable bodyportion is in an expanded state, wherein said pharmaceutically activeagent resides in between said body portion and said cover. During use ofthe inflatable balloon, said pharmaceutically active agent is releasedfrom said inflatable body portion.

In certain embodiments, said cover is an expandable cover, and wherein,when said cover is in an expanded state, a permeability of said cover isgreater than the permeability of said cover when said cover is in anon-expanded state.

The device is an inflatable balloon which may be positioned on acatheter or other flexible shaft device. In an embodiment, the balloonsegment of the catheter is encapsulated, coated or otherwise providedwith at least one therapeutic or pharmaceutically active agent such aseverolimus, tacrolimus, sirolimus, zotarolimus, biolimus, rapamycin oran equivalent active pramaceutical ingredient, which is encapsulated orsuspended in a biocompatible matrix.

In certain embodiments, the pharmaceutically active agent can beembedded, layered, suspended or dissolved in a matrix such as gel. Thegel or matrix may be a hydrogel which can be dried and re-hydrated priorto the expansion of the balloon in vivo. In one embodiment, the gelmatrix comprises a hydratable suspension. In one embodiment, the gelmatrix may be dehydrated.

In certain embodiments, the balloon and the matrix are encapsulated byan expandable cover.

The expandable cover may be a polymer membrane (or an expandablemembrane), having a plurality pores (having an average size). In certainembodiments, the average size of said pores is greater in an expandedstate of said membrane than in a non-expanded state of said membrane. Incertain embodiments, the membrane is non-permeable or semi-permeable inan unexpanded state. When the balloon expands, the permeability of thecover may increase. For example, during inflation of the ballooncatheter, the expansion of the balloon body stretches the membrane, andpores or channels may form in or throughout the cover which increase indiameter as the balloon expands. The diameter of the pores or materialporosity may range from about 1 μm to about 100 μm, or from about 20 μmto about 80 μm or about 1 μm to 50 μm, when the membrane is expanded.The membrane may be hydrophobic and non-permeable when non-expandedwhile the matrix is being extruded through the membrane once the balloonis being inflated and exerts pressure on the matrix.

In certain embodiments, the inflatable balloon comprises a longitudinalaxis and a plurality of pleats folded along the longitudinal axis of theballoon.

The balloon may be coated with at least one pharmaceutically activeagent.

The cover may be formed as an expandable tubular sleeve that enclosesthe balloon, while being substantially compliant with said balloon inits non-inflated state. In certain embodiments, the cover comprises atubular sleeve that is provided over at least said inflatable bodyportion of said balloon, and in that said cover lies substantiallycompliant with said body portion of the balloon in the non-inflatedstate of said balloon.

In certain embodiments, the cover may be formed from a braid.

The cover may comprise a porous layer (e.g., an elastomeric porouslayer) having a porosity. In one embodiment, the porosity of said layeris greater in an expanded state of said layer than in a non-expandedstate of said layer.

When expanded, the porosity of the expandable cover may be greater thanthe porosity of the expandable cover when it is in an unexpanded state.The expandable cover may have a plurality of pores. After expansion, theporosity of the expandable cover in the expanded state ranges from about20% to about 400% greater, from about 50% to about 300% greater, or fromabout 100% to about 200% greater, as compared with the unexpanded state.

The pharmaceutically active agent is suspended in a matrix. The matrixcan be a gel such as a hydrogel. During expansion of the balloon, thetherapeutic agent is released to a body cavity such as a blood vessel orother bodily lumen.

The cover can be formed from a polymer such as ePTFE or ultra-highmolecular weight polyethylene.

In certain embodiments, the pharmaceutically active agent may besuspended or encapsulated in a plurality of biodegradable nano-sizedand/or micron-sized bodies, such as beads, spheres or cells that areseveral nanometers to a few micrometers in size. These biodegradablebodies may be suspended and distributed (e.g., homogeneously) in a(further) matrix. In one embodiment, the inflatable body portion of theballoon is coated with said matrix, containing said bodies. In oneembodiment, the cover is coated with said matrix, containing saidbodies. In one embodiment, said bodies are suspended in a soluble film,which may be wrapped around at least the inflatable body portion of saidballoon. The said film may comprise a water degradable matrix thatcontains said bodies. In one embodiment, said film is a solvent cast orextruded thin film formulation containing said bodies. In oneembodiment, said film comprises a polysaccharide polymer consisting ofmaltotriose units, inter alia known as pullulan. In one embodiment, saidfilm contains between 5% and 30% (w/w) of the pharmaceutically activeagent. In one embodiment, said film comprises one or more auxiliaryagents from a group comprising stabilizers, thickening agents, andpermeability enhancers.

Particularly said (further) matrix may be formed into a tube, spiral cuttubular construction, tape or film that may be wrapped around saidinflatable portion of said balloon. The film may be a water-swellabledehydrated film that degrades and dissolves one (in vivo) in contactwith water. The nano/micro bodies are then vented or pressed through thecover and into surrounding tissue of a body lumen, particularly anartery or vein, while the balloon is inflated in vivo and will thenbased on composition of drug release said pharmaceutically active agentover a prolonged period of time. Typically said prolonged period of timemay be over 25 days, particularly over 30 days. The bodies mayincorporate as much as between 5% w/w to 30% w/w of the activepharmaceutical ingredient.

The film may comprise a polysaccharide polymer consisting of maltotrioseunits, inter alia known as pullulan. Pullulan is a polysaccharidepolymer consisting of maltotriose units, also known asα-1,4-;α-1,6-glucan. Three glucose units in maltotriose are connected byan α-1,4 glycosidic bond, whereas consecutive maltotriose units areconnected to each other by an α-1,6 glycosidic bond. Pullulan isproduced from starch by the fungus Aureobasidium pullulans. Pullulan ismainly used by the cell to resist desiccation and predation. Thepresence of this polysaccharide also facilitates diffusion of moleculesboth into and out of the cell.

The film may comprise one or more auxiliary agents from a groupcomprising stabilizers, thickening agents and permeability enhancers.

In some embodiments, less than about 10% (w/w) of the pharmaceuticallyactive agent is released from the balloon at body temperature in aboutone hour in an aqueous environment, when the balloon is non-inflated. Incertain embodiments, greater than about 50% (w/w), 60% (w/w), 70% (w/w)or 80% (w/w) of the pharmaceutically active agent is released from theballoon at body temperature in about one hour in an aqueous environment(such as PBS), when the balloon is inflated.

In certain embodiments, the pharmaceutically active agent comprises ananti-proliferative agent such as everolimus, tacrolimus, sirolimus,zotarolimus, biolimus, rapamycin, an M-tor inhibitor active agent, or apharmaceutically equivalent agent.

In certain embodiments, between 5% and 30% w/w of said pharmaceuticallyactive agent is present in the matrix.

The present disclosure also provides for a catheter comprising theinflatable balloon as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the guidewire and the balloon in an unexpanded state.

FIG. 2 shows the balloon in an expanded state.

FIG. 3 shows a cross sectional view of the balloon in an unexpandedstate with pleats and an expandable cover.

FIG. 4 shows the balloon in an expanded state with extrusion of thematrix.

FIG. 5 shows a close-up view of FIG. 4.

FIG. 6 shows a cross sectional view of the balloon in an expanded statewith extrusion of the matrix/gel.

FIG. 7 shows the gel matrix forming a thin film wrapping around theballoon in a spiral configuration.

FIG. 8 shows a cross sectional view of the balloon in an unexpandedstate enclosed by an expandable cover and a gel matrix formed in a wrap.

FIG. 9 shows the matrix formed as spiral wrap, enclosed with anexpandable cover, and a close-up view of the balloon with extrusion ofthe gel through the pores/slits.

FIGS. 10A-10G illustrate the following possible configurations whichshould be considered non-limiting.

FIG. 10A. The balloon is shown with the tape wrapped around the proximalportion of the balloon.

FIG. 10B. The balloon is shown with the tape wrapped around the distalportion of the balloon.

FIG. 10C. The balloon is shown with four (4) wraps of the tape aroundthe balloon.

FIG. 10D. The balloon is shown with two different tapes, Tape 1 and Tape2, wrapped around the balloon.

FIG. 10E. The balloon is shown with two different tapes, Tape 1 and Tape2, wrapped around the proximal, Tape 1, and distal, Tape 2, portions ofthe balloon.

FIG. 10F. The Pullulan is shown with two different APIs, APi₁ and API₂,suspended in a nanoparticle, API₁ and a liposome, API₂.

FIG. 10G. The balloon is shown with four different Tapes, Tapes 1-4,aligned longitudinally along the balloon.

DETAILED DESCRIPTION

The present disclosure provides for an inflatable balloon which isenclosed by an expandable cover which becomes increasinglyporous/permeable during expansion. The balloon is coated or enclosedwith a matrix that contains a pharmaceutically active agent. Duringexpansion of the balloon, the pharmaceutically active agent is releasedthrough the expandable membrane into a body cavity such as an artery orvein. The present invention also provides for a method of treating adisease or condition by delivering the inflatable balloon to the artery,vein or body cavity.

The inflatable balloon can be an angioplasty balloon which is positionedon a catheter or other flexible shaft device. The balloon is coated withat least one pharmaceutically active agent. The coating may be in theform of any biocompatible matrix (as used herein, coating refers tocoating, covering, enclosing or disposing (disposed) between the balloonand the expandable cover). For example, the biocompatible matrix may bea semisolid such as a gel. The coating incorporating thepharmaceutically active agent may also be wrapped around the balloonusing a tape which may be in the form of a spiral, spiral-cut tube orspiral-cut wrapping enclosing the balloon. The balloon may be wrapped 1,2, 3, 4, 5, 6, 7, 8, 9, 10 . . . n times with the biocompatible matrix.The pharmaceutically active agent may be suspended, embedded ordissolved in a biocompatible matrix such as gel. The pharmaceuticallyactive agent may be miscible or immiscible with the biocompatiblematrix. In certain embodiments, the pharmaceutically active agent may beencapsulated in a particle such as a liposome, nanoparticle or otherparticle such as, cyclodextran. The gel may be a hydrogel which can bedried and then re-hydrated prior to the expansion of the balloon in vivoor in vitro.

As used herein, the term “a pharmaceutically active agent” isinterchangeable with the terms “a pharmaceutical agent” or “drug”.

The balloon and the biocompatible matrix are enclosed by an expandablecover which conforms to the balloon (as used herein, enclosed, enclosingor encloses refers to surrounding, covering, enclosing orencapsulating). The expandable cover may entirely enclose the entireballoon or only a portion of the balloon. There exists an annular spaceor lumen between the expandable cover and the balloon which may besealed, i.e., not in fluid communication with the catheter oralternatively, the annular space or lumen may be in fluid communicationwith the catheter. Preferably, the expandable cover is semi-permeable orporous when the balloon is in an unexpanded state. When the balloonexpands, porosity or permeability of the expandable cover to theexternal environment, e.g., plasma, blood, body fluid, etc. increases.For example, during inflation of the balloon catheter, the expansion ofthe balloon stretches or radially expands the expandable cover. As aresult of such expansion, pores or channels may form in the expandablecover; these pores or channels increase in size or number as the balloonexpands. When the coated balloon is initially exposed to an aqueousenvironment, e.g., plasma or phosphate buffered saline, for a definedperiod of time, fluid is able to penetrate the expandable cover andbegin to solubilize the matrix. This initial solubilization facilitatesexpansion of the coating (fluidizes) as the expandable balloon isinflated. As the balloon expands, plasma or other aqueous fluids, cancontinue to diffuse into the annular space or lumen between theexpandable cover and the balloon. Upon inflation, the coating continuesto dissolve, releasing the pharmaceutically active agent through theexpandable cover into the body cavity, such as as the artery or vein (asused herein, release refers to release, extrusion, squeezing, burst ordiffusion of the pharmaceutically active agent either alone orencapsulated in a microsphere, liposome, nanoparticle (e.g., nanogel),cyclodextran or other particle or in conjunction with the biocompatiblematrix through the expandable cover). In one embodiment, the coating isinitially dehydrated. Once in contact with the plasma or other aqueousfluid, the coating becomes fully rehydrated and then dissolves. The rateof release of the pharmaceutically active agent is variable and isdependent on a number of different variables, including the rehydrationprocess and nature of the biocompatible matrix, the rate of extent ofexpansion of the balloon and the degree of porosity/permeability of theexpandable cover.

Diseases that can be treated with the present balloon, include, but arenot limited to, both coronary artery and peripheral artery diseases aswell as others. Non-limiting examples of the diseases or conditions thatcan be treated by the present balloon or method include atherosclerosis,coronary artery atherosclerosis disease (CAD), peripheral arteryatherosclerosis disease (PAD), narrowing of an artery, etc.Atherosclerosis is one of the leading causes of death and disability inthe world.

Atherosclerosis involves the deposition of fatty plaques on the luminalsurface of arteries. The deposition of fatty plaques on the luminalsurface of the artery causes narrowing of the cross-sectional area ofthe artery. Ultimately, this deposition blocks blood flow distal to thelesion causing ischemic damage to the tissues supplied by the artery.Coronary arteries supply the heart with blood. Coronary arteryatherosclerosis disease (CAD) is the among most common, serious,chronic, life-threatening illness in the United States. According to theCenters for Disease Control, 370,000 people die annually from CAD and735,000 Americans have a heart attack or myocardial infarction(https://www.cdc.gov/heartdisease/facts.htm, retrieved, Feb. 5, 2017).Narrowing of the coronary artery lumen causes destruction of heartmuscle resulting first in angina, followed by myocardial infarction andfinally death.

Narrowing of the arteries can occur in vessels other than the coronaryarteries, including carotid, aortoiliac, infrainguinal, distal profundafemoris, distal popliteal, tibial, subclavian and mesenteric arteries.The prevalence of peripheral artery atherosclerosis disease (PAD)depends on the particular anatomic site affected as well as the criteriaused for diagnosis of the occlusion, but as many 8.5 million people inthe United States are estimated to suffer from PAD(https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_pad.htm,retrieved, Feb. 5, 2017) . Traditionally, physicians have used the testof intermittent claudication to determine whether PAD is present.

The present invention also provides for a method of treating any bodycavity by releasing a pharmaceutically active agent from an inflatableballoon through an expandable cover into body cavities other thanvascular spaces. For example, the genitourinary system, including, theurethra, bladder, ureters, penis and vagina, gastrointestinal system,such as the esophagus, stomach, small intestine or colon, therespiratory system, including, the trachea, bronchi and alveoli can betreated with the balloon of the present invention. Vascular spaces otherthan coronary arteries may also be treated, including, the aorta, venacava (inferior and superior) or neurovascular arteries, e.g., carotidarteries, basilar arteries. The coated balloon of the present inventionmay also be used to create a cavity within a potential space in thebody, e.g., muscle, vascular intima or fibrotic tissue. Thepharmaceutically active agent is then released into the new body cavitycreated from the potential space, e.g., within a muscle.

Other diseases may be treated with the coated balloon of the presentinvention, including, inflammatory diseases and cancers. Cancers thatcan be treated with coated balloon of the present invention include, butare not limited to, bladder, lung cancer, ear, nose and throat cancer,leukemia, colon cancer, melanoma, pancreatic cancer, mammary cancer,prostate cancer, breast cancer, hematopoietic cancer, ovarian cancer,basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer;breast cancer; cervical cancer; choriocarcinoma; colon and rectumcancer; connective tissue cancer; cancer of the digestive system;endometrial cancer; esophageal cancer; eye cancer; cancer of the headand neck; gastric cancer; intra-epithelial neoplasm; kidney cancer;larynx cancer; leukemia including acute myeloid leukemia, acute lymphoidleukemia, chronic myeloid leukemia, chronic lymphoid leukemia; livercancer; lymphoma including Hodgkin's and Non-Hodgkin's lymphoma;myeloma; fibroma, neuroblastoma; oral cavity cancer (e.g., lip, tongue,mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer;retinoblastoma; rhabdomyosarcoma; rectal cancer; renal cancer; cancer ofthe respiratory system; sarcoma; skin cancer; stomach cancer; testicularcancer; thyroid cancer; uterine cancer; cancer of the urinary system, aswell as other carcinomas and sarcomas.

Inflammatory diseases, include, but are not limited to, rheumatoidarthritis, systemic lupus eythematosis (SLE), Crohn's diseases or othercollagen vascular diseases. Infections diseases resulting from bacteria,viruses or prions may also be treated with the balloon of the presentinvention.

The structure of the expandable cover is preferably elasticallycompliant and expandable. The expandable cover may be constructed in theform of a weave, sheet, tube, film, cast, sleeve, tape or any otherdesired structural configuration which permits the expandable cover tobe conformal to the balloon. The expandable cover further comprises aplurality of holes, pores, slits or perforations. Alternatively, theholes, pores, slits or perforations may be formed from a porous networkof fibrils, or from a variable density of a fibril matte. Various typesof expandable covers may be used, including those which are elastomericand where the pores open when the balloon is inflated (and/or the coveris expanded), and retract when the balloon is deflated (and/or the coveris unexpanded). The expandable cover may comprise, e.g. silicone, latex,polyurethane, and those other materials which are plastically deformedas the material is stretched, thus opening up pores (see discussion ofmaterials, infra.). When the expandable cover is in an unexpanded state,the holes, pores, slits or perforations are substantially closed, sothat the permeability of the expandable cover as measured by release ofthe pharmaceutically active agent from the balloon (e.g., into anaqueous environment) is less than about 50% (w/w), less than about 25%(w/w), less than about 15% (w/w), less than about 10% (w/w), or lessthan about 5% (w/w) over a defined period of time as set for the below.As used herein, w/w means the weight of the pharmaceutically activeagent released at any time, t, over total weight of pharmaceuticallyactive agent coated on the balloon; % w/w means w/w X 100.

In vivo release of the pharmaceutically active agent into a vascularspace may be simulated in vitro by incubating the balloon which iscoated with a pharmaceutically active agent and enclosed with anexpandable cover in an aqueous bath including a buffer such as phosphatebuffered salined (PBS). The release of the pharmaceutically active agentto the aqueous bath (e.g., the buffer) after expansion of the balloon isthen assayed. Release profiles, both absolute w/w as well as kinetic

$J = {{- D}\frac{dC}{dx}}$

(see discussion below), of the pharmaceutical active agent are measured.The concentration of the pharmaceutically active agent in the aqueousenvironment may be measured using any means, including, but not limitedto, high pressure liquid chromatography (HPLC) or specific immunologicalassays. For example, the amount of the pharmaceutically active agentreleased through the expandable cover within about 1 hour when incubatedat about 4° C., about 20-25° C. or about 37° C. in an aqueousenvironment such as PBS, plasma, blood, a body fluid, or other aqueousmedium is assayed. Various time points may be used to assess release ofthe pharmaceutically active agent when the balloon is in an unexpandedstate or an expanded state, including, but not limited to, within about30 seconds, within about 1 minute, within about 2 minutes, within about3 minutes, within about 4 minutes, within about 5 minutes, within about6 minutes, within about 8 minutes, within about 9 minutes, within about10 minutes, within about 15 minutes, within about 20 minutes, withinabout 25 minutes, within about 30 minutes, within about 35 minutes,within about 40 minutes, within about 45 minutes, within about 50minutes, within about 55 minutes, within about 1 hour, within about 2hours, within about 3 hours, within about 4 hours, within about 5 hours,within about 6 hours, within about 7 hours, within about 8 hours, withinabout 1-10 minutes, within about 10-100 minutes or within about 50 -200minutes.

After the expandable balloon has been advanced to the target site, theoperator, e.g., the interventional cardiologist, deploys the balloon byinflating it. When the expandable cover is expanded due to expansion ofthe balloon, the porosity or permeability of the expandable coverincreases. As discussed previously, plasma or other aqueous fluids canthen diffuse into the annular space or lumen between the expandablecover and the balloon. The coating is then dissolved (totally orpartially), releasing the pharmaceutically active agent through theexpandable cover into the body cavity, such as as the artery or vein tothe pharmaceutically active agent. In one embodiment, the coating isinitially dehydrated during application to the balloon and thenrehydrated after contact with the aqueous environment, e.g., plasma.When the expandable cover is in an expanded state, the permeability ofthe expandable cover as measured by release of the pharmaceuticallyactive agent into an aqueous environment is about 100% (w/w), 95% (w/w),90% (w/w), 80% (w/w), 70% (w/w), 60% (w/w), 50% (w/w), 40% (w/w), 30%(w/w) or 20% (w/w). The assay for the pharmaceutically active agent canbe performed as described above at 4° C., 20-25° C. or 37° C. in anaqueous environment such as PBS at 1 hour or for the time periods setforth above.

Any desired amount of pharmaceutically active agent can be applied tothe balloon. For example, the amount of the pharmaceutically activeagent that is coated on or impregnated on the balloon (e.g., the coverand/or matrix) may range from about 10 to 50,000 μg, including, 10, 20,30, 40, 50, 60, 70, 80, 90, 100, 500, 1000, 10,000, 20,000, 30,000,40,000 and 50,000 μg. The total surface load of the pharmaceuticallyactive agent on the balloon may range from about 1 μg/mm² to about 200μg/mm², including, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50,100, 150 or 200 μg/mm². The amounts of the active agent present on theballoon in the biocompatible matrix can range from 2 μg/mm² to 10μg/mm², 2.5 μg/mm² to 5 μg/mm², 1 μg/mm² to 2 μg/mm², 2 μg/mm² to 15μg/mm², 5 μg/mm² to 25 μg/mm² or 25 μg/mm² to 40 μg/mm². Because thecoating can be applied in any form, e.g., a tape or wrapping and theannular space or lumen between the balloon and expandable cover may varyas well. Accordingly, the quantity of the pharmaceutically active agentmay vary significantly, with loadings of the pharmaceutically activeagent ranging up to 10,000 -50,000 μg.

Permeability of the expandable cover may be a function of the porosityof the expandable cover. When the expandable cover is in an expandedstate, the permeability or porosity of the expandable cover may rangefrom about 20% to about 400%, from about 50% to about 300%, or fromabout 100% to about 200% greater than the permeability or porosity ofthe expandable cover when the expandable cover is in an unexpanded orcompressed state. To calculate % ranges here, the permeability orporosity in the expanded state is divided by the permeability orporosity, respectively, in the unexpanded state and then multiplied by100. Percentage differences also include, 10%, 20%, 30%, 40%, 50% 60%70%, 80%, 90% 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%and the like.

“Porosity” refers to a measure of the void spaces in a material, and ismeasured as a percentage of void space to solid material ranging between0 - 100%. Porosity may be determined according to the equation:Porosity=(1−d₁/d₂)×100, where di is the density of the material which isdetermined from the material weight and the material volume asascertained from measurements of the sample dimensions, and d₂ is thedensity of the solid portion of the sample (see, e.g., U.S. Pat. No.7,445,735 and EP 0464163B1). The volume of the solid portion of thesample can be measured, for example, using a Quantachromestereopycnometer (Quantachrome Corp.). The average diameter of the poresof the expandable structure can be determined by mercury intrusionporosimetry using an Autoscan mercury porosimeter (Quantachrome Corp.).Mercury Intrusion/Extrusion is based on forcing mercury (a non-wettingliquid) into a porous material under tightly controlled pressures. Sincemercury does not wet most substances and will not spontaneouslypenetrate pores by capillary action, it must be forced into the voids ofthe sample by applying external pressure. The pressure required to fillthe voids is inversely proportional to the size of the pores. Only asmall amount of force or pressure is required to fill large voids,whereas much greater pressure is required to fill voids of very smallpores. U.S. Pat. No. 7,445,735. The porosimetry can also be conductedusing other suitable non-wetting liquid besides mercury. Other methodsthat may be employed to measure porosity include ellipsometricporosimetry, water saturation method, water evaporation method, andnitrogen gas adsorption method. The diameters of the pores in theexpandable cover when expanded may range from about 1 μm to about 100μm, from about 10 μm to about 100 μm, from about 20 μm to about 80 μm,from about 40 μm to about 60 μm or about 20 μm to about 50 μm.

The pharmaceutically active agent can be uniformly delivered over aperiod of time, t, to the body cavity. The pharmaceutically active agentmay be released through the expandable cover following zero-orderkinetics with no burst effect. As used herein, the term “zero-orderkinetics” refers to a release profile where the pharmaceutically activeagent is released at a rate independent of time and the concentration ofthe pharmaceutically active agent incorporated into the balloon.Zero-order release ensures that a steady amount of pharmaceuticallyactive agent is released over desired length of time, minimizingpotential peak/trough fluctuations and side effects, while maximizingthe amount of time the pharmaceutically active agent's concentrationsremain within the therapeutic window. The release rate may be calculatedusing standard methodology,

$J = {{- D}\frac{dC}{dx}}$

Where drug flux is J and the change in drug concentration over time canbe represented as:

$\frac{\partial C}{\partial t} = {D\frac{\partial^{2}C}{\partial x^{2}}}$

The term “drug”, “pharmaceutically active agent” or “pharmaceuticalagent” are used interchangeably here. Release rates may also bediffusion or erosion driven. Fu et al. Drug Release Kinetics andTransport Mechanisms of Non-degradable and Degradable Polymeric DeliverySystems. Expert Opin Drug Deliv. 2010 April; 7(4): 429-444.Alternatively, the release of the pharmaceutically active agent may actas a burst with immediate release into the body cavity.

The thickness of the expandable cover may range from about 0.1μm toabout 300 μm or from about 1 μm to about 150 μm. Other ranges areincluded herein, such as 50, 100, 150, 200, 250 or 300 μm. Theexpandable cover deforms without cracking when it is subjected tostretch or elongation and undergoes plastic and/or elastic deformation.After the balloon is deflated, the expandable cover returns to itsunexpanded state without being broken, torn, inverted or rolled-backonto itself. The expandable cover may comprise any suitable materials,including synthetic and non-synthetic materials. The expandable covermay also comprise mixtures of synthetic and non-synthetic materials.Examples of the synthetic material, include high density, high molecularweight polyethylene (HDHMWPE), ultra high molecular weight polyethylene(UHDHMWPE), expanded poly(tetrafluoroethylene) (ePTFE), ethylene vinylacetate, latexes, urethanes, fluoropolymer, polyvinyl alcohol(PVA)-cross linked hydrogel, polysiloxanes,styrene-ethylene/butylene-styrene block copolymers, aliphaticpolyesters, and mixtures and copolymers thereof, polydimethylsiloxane(PDMS) (Silicone) or polyurethane foam, e.g., HYPOL™. The expandablematerial may be woven as a braid with a latticework of polymericmonofilaments such as a tubular interbraided sleeve of polymericmultifilament yarns. U.S. Pat. No. 5,957,974.

In one embodiment, the expandable cover is constructed of medical gradesilicone. In another embodiment, the cover is an elastomer. In a thirdembodiment, the elastomer is a high-strength thermoplastic elastomer.This high-strength thermoplastic elastomer can be a styrenic blockcopolymer, a polyolefin blend, an elastomeric alloy, a thermoplasticpolyurethane, a thermoplastic copolyester, or a thermoplastic polyamide.The high-strength thermoplastic elastomer may be formed from apolyester-polyether copolymer or a polyamide-polyether copolymer. Thehigh-strength thermoplastic elastomer can also be a nylon. Examples ofthe non-synthetic material include, but are not limited to, collagen,fibrin, elastin, extracellular matrix components as well as mixturesthereof.

The coating may be in the form of any biocompatible matrix. The coatingmay be applied directly on the exterior surface of the balloon, or maybe applied on the interior or inner surface of the expandable cover.Alternatively, the pharmaceutically active agent may be disposed betweenthe outer surface of the balloon and interior or inner surface of theexpandable cover in a biocompatible matrix. The coating incorporatingthe pharmaceutically active agent may also be wrapped around the balloonusing a tape which may be in the form of a spiral, spiral-cut tube orspiral-cut wrapping enclosing the balloon. The balloon may be wrapped 1,2, 3, 4, 5, 6, 7, 8, 9, 10 . . . n times with the biocompatible matrix.The biocompatible matrix containing the pharmaceutically active agentcan be applied to the balloon or expandable cover using standardtechniques to cover either the entire or only a partial surface of theballoon or the expandable cover. The coating may form a single layer ofa homogeneous mixture of a pharmaceutically active agent(s) and abiocompatible matrix, e.g., gel, or be present in a defined geometricpattern, e.g., a dot matrix pattern.

The coating may form a single layer or multiple layers such as acontinuous wrapping around the balloon. The balloon may be dipped orsprayed with a liquid solution comprising at least one pharmaceuticallyactive agent. After each layer is applied, the balloon may be driedbefore application of the next layer. The thickness of the layerincorporating the pharmaceutically active agent may range from about0.1μm to about 150 μm, from about 1 μm to about 100 μm, from about 10 μmto about 50 μm, or from about 20 μm to about 30 μm. Alternatively,multiple layers of the pharmaceutically active agent/biocompatiblematrix composition can be applied on the surface of the balloon or coverin these or other thickness ranges. For example, different layers of twoor more pharmaceutically agents can be coated on the balloon orexpandable cover so that a particular pharmaceutically active agent canbe released into the body cavity first, followed by subsequent releaseof a second pharmaceutically active agent.

The biocompatible matrix may comprise a water soluble material orwater-swellable material. The pharmaceutically active agent may bedispersed uniformly or nonuniformly (e.g., particulates such asliposomes or nanoparticles) within the biocompatible matrix. Thebiocompatible matrix may comprise a water soluble material which may bedehydrated after application and then rehydrated after insertion intothe body cavity by the operator. “Water soluble material” refers tomaterial that dissolves, hydrolyzes, breaks-down, dissolves ordisintegrates in contact with water or other aqueous physiologicalfluid, such as plasma or interstitial fluid. As the balloon expands, theexpandable cover also expands, accompanied by an increase inpermeability to the plasma or other physiological fluids. The watersoluble material within the pharmaceutically active agent coatingdissolves and the pharmaceutically active agent is released into thebody cavity. The length of time that is needed for the biocompatiblematrix to be dissolved may vary and be less than about 4 hours, 2 hours,less than about 1 hour, less than about 30 minutes, less than about 10minutes, less than about 5 minutes, less than about 1 minute, less thanabout 30 seconds or less than about 5 seconds.

The biocompatible matrix may comprise a mixture of water insoluble andwater soluble materials. Examples of such combinations, include shellacand polyvinylpyrollidone, and ethyl cellulose and hydroxypropylmethylcellulose. The biocompatible matrix may also comprise water swellablematerial. Water soluble or water swellable material may comprise apolysaccharide, such as dextran, alginate, amylose, amylopectin,carrageenan, carboxymethyl cellulose, gellan, guar gum, polysaccharideconjugate vaccines, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose, amylopectin,starch derivatives, hyaluronic acid, starch derivatives, xantan,xyloglucan, chitosan-based hydrogel, peptidoglycan, and progeogl yeans.Water soluble or water swellable material may also comprise a simplecarbohydrate, such as glucose, maltose, lactose, fructose, sucrose,galactose, glucosamine, galactosamine, muramic acid, glucruronate,gluconate, fucose, trehalose, a synthetic polymer, such as polyvinylalcohol, polyvinylpyrrolidone, polyethylene glycol, propylene glycol,polyoxyethylene derivatives, a polypeptide, such as elastin, polyvinylamine or poly(L-lysine), uncrosslinked hydrogel, crosslinked hydrogel,polyacrylic acid or any other cross-linked water swellable polymers.Examples of hydrogel materials include carboxymethyl cellulose (CMC),hydroxypropylmethyl cellulose (HPMC), amylopectin, starch derivatives,hyaluronic acid, or their combinations (WO2007US0074123).

The biocompatible matrix that incorporates the pharmaceutical agent mayalso comprise any desired biocompatible, non-toxic material. Examples ofsuch biocompatible materials include, poly(lactide-co-glycolide),polyesters such as polylactic acid, polyglycolic acid, polyanhydride,polycaprolactone, polyhydroxybutyrate valerate, or mixtures orcopolymers thereof. In one embodiment, the biocompatible matrix mayfurther comprise naturally occurring substances such as collagen,fibronectin, vitronectin, elastin, laminin, heparin, fibrin, cellulose,carbon or extracellular matrix components. Polymers which can be used inthe matrix include poly(lactide-co-glycolide); poly-DL-lactide,poly-L-lactide, and/or mixtures thereof and can be of various inherentviscosities and molecular weights. In one embodiment, poly(DLlactide-co-glycolide) can be used. The poly-DL-lactide material can bein the form of homogeneous composition and when solubilized and dried,it can form a lattice of channels in which pharmaceutical substances canbe trapped for delivery to the tissues. In a further embodiment, thecoating composition comprises a nonabsorbable polymer, such as ethylenevinyl acetate (EVAC) , polybutyl- methacrylate (PBMA) andmethylmethacrylate (MMA).

Other examples of bioabsorbable polymers that may be used with themethods of the present invention include, aliphatic polyesters, bioglasscellulose, chitin collagen copolymers of glycolide, copolymers oflactide, elastin, tropoelastin, fibrin, glycolide/1-lactide copolymers(PGA/PLLA), glycolide/trimethylene carbonate copolymers (PGA/TMC),hydrogel lactide/tetramethylglycolide copolymers, lactide/trimethylenecarbonate copolymers, lactide/-ε-caprolactone copolymers,lactide-σ-valerolactone copolymers, L-lactide/d1-lactide copolymers,methyl methacrylate-N-vinyl pyrrolidone copolymers, modified proteins,nylon-2 PHBA/γ-hydroxyvalerate copolymers (PHBA/HVA), PLA/polyethyleneoxide copolymers, PLA-polyethylene oxide (PELA), poly (amino acids),poly (trimethylene carbonates), poly hydroxyalkanoate polymers (PHA),poly(alklyene oxalates), polybutylene diglycolate), poly(hydroxybutyrate) (PHB), poly(n-vinyl pyrrolidone), poly(ortho esters),polyalkyl-2-cyanoacrylates, polyanhydrides, polycyanoacrylates,polydepsipeptides, polydihydropyrans, poly-d1-lactide (PDLLA),polyesteramides, polyesters of oxalic acid, polyglycolide (PGA),polyiminocarbonates, polylactides (PLA), polyorthoesters,poly-p-dioxanone (PDO), polypeptides, polyphosphazenes, polysaccharides,polyurethanes (PU), polyvinyl alcohol (PVA), poly-β-hydroxypropionate(PHPA), poly-β-hydroxybutyrate (PBA), poly-σ-valerolactone,poly-β-alkanoic acids, poly-β-malic acid (PMLA), poly-ε-caprolactone(PCL), pseudo-Poly(Amino Acids), starch, trimethylene carbonate (TMC)and tyrosine based polymers. U.S. Pat. No. 7,378,144.

Polymers used for controlled drug delivery may also be used with thecoating. Examples of such polymers, include, polyanhydrides andpolyesters, polymers and copolymers of lactic acid, glycolic acid,hydroxybutyric acid, mandelic acid, caprolactone, sebacic acid,1,3-bis(p-carboxyphenoxy)propane (CPP), bis-(p-carboxyphenoxy)methane,dodecandioic acid (DD), isophthalic acid (ISO), terephthalic acid,adipic acid, fumaric acid, azeleic acid, pimelic acid, suberic acid(octanedioic acid), itaconic acid, biphenyl-4,4′-dicarboxylic acid andbenzophenone-4,4′-dicarboxylic acid. Polymers may be aromatic,aliphatic, hydrophilic or hydrophobic.

The polymer forming the biocompatible matrix may comprise apolysaccharide polymer consisting of maltotriose units, also referred toas pullulan. Pullulan is a polysaccharide polymer consisting ofmaltotriose units, also known as α-1,4-;α-1,6-glucan. Three glucoseunits in maltotriose are connected by an α-1,4 glycosidic bond, whereasconsecutive maltotriose units are connected to each other by an α-1,6glycosidic bond. Pullulan may be produced from starch by the fungusAureobasidium pullulans.

The pharmaceutically active agent may be dispersed within and/or on asponge-like membrane or layer, made of a non-hydrogel polymer having aplurality of voids. The sponge like membrane or layer alternatively mayalso be constructed out of a polymer based fibril network orscaffolding, resulting in void spaces existing within this fibrous orfibril nodal network. The pharmaceutically active agent may be infusedinto the voids of the sponge membrane or layer that is positioned on theexternal surface of the balloon and lie or be disposed between the outermembrane of the balloon and the inner wall of the expandable cover. Whenthe balloon is radially expanded, the sponge membrane or layer stretchesaround the circumference of the balloon and becomes thinner, opening andenlarging the voids. As a result, the pharmaceutically active agent isexpelled or “squeezed out” through the voids of the sponge membrane orlayer. The sponge membrane or layer may be prepared by dissolving anon-hydrogel polymer in a solvent and an elutable particulate material.After the sponge membrane or layer composition is cured, it is exposedto a solvent, e.g. water or PBS, which causes the particulate materialto elute from the polymer, leaving a sponge membrane or layer having aplurality of voids therein. The sponge coating is then exposed to abiologically active material to load the sponge membrane or layer withsuch material. Such material may be loaded into the coating by diffusionor other means. Non-hydrogel polymer(s) useful for forming the spongemembrane or layer are biocompatible. Non-hydrogel polymers are polymersthat when a drop of water is added on top of a film of such polymer, thedrop will not spread. Examples of such polymers include, withoutlimitation, polyurethanes, polyisobutylene and its copolymers,silicones, and polyesters. Other suitable polymers include polyolefins,polyisobutylene, ethylene-alphaolefin copolymers, High Density HighMolecular Weight Polyethelene (HDHMWPE), acrylic polymers andcopolymers, vinyl halide polymers and copolymers such as polyvinylchloride, polyvinyl ethers such as polyvinyl methyl ether,polyvinylidene halides such as polyvinylidene fluoride andpolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics such as polystyrene, polyvinyl esters such as polyvinylacetate; copolymers of vinyl monomers, copolymers of vinyl monomers andolefins such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetatecopolymers, polyamides such as Nylon 66 and polycaprolactone, alkydresins, polycarbonates, polyoxyethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, carboxymethylcellulose, collagens, chitins, polylactic acid, polyglycolic acid, andpolylactic acid-polyethylene oxide copolymers. U.S. Pat. No. 6773447.U.S. Patent Publication No. 20040006359.

The biocompatible matrix may also comprise an organogel, such as apoly(ethylene), L-alanine, sorbitan monostearate, Eudragit or lecithinorganogel. Gupta et al. World J. Pharmacy & Pharmaceutical Sciences3(9):150-163 (2014). Alternatively, the gels may comprise a sol-gel.Niederberger et al. Metal Oxide Nanoparticles in Organic Solvents,Synthesis, Formulation. Assembly and Applications. Springer (2009).

The biocompatible matrix may comprise a thin film. Karki et al. Thinfilms as an emerging platform for drug delivery. Asian J. PharmaceuticalSciences 574 (2016). Thin films comprise a thin and flexible layer ofpolymer with or without a plasticizer. Id. In certain embodiments, athin film dissolves more rapidly, i.e., quick-dissolve, than otherconventional dosage forms. Id. Thin films may also be mucoadhesive. Id.The thin film may be formed in any shape or size. In certainembodiments, the thin films may have a thickness of about 500 μm toabout 1,500 μm; and when dried the thin films may have a thickness fromabout 3 μm to about 250 μm. The thin film may comprise polymersincluding, but not limited to, Hydroxypropyl methylcellulose (HPMC),Carboxymethyl cellulose (CMC), Hydroxypropyl cellulose (HPC), Poly(vinyl pyrrolidone) (PVP), Poly (vinyl alcohol) (PVA), Poly (ethyleneoxide) (PEO), Pullulan, Chitosan, Sodium alginate, Carrageenan, Gelatin,or combinations thereof.

The biocompatible matrix may comprise a bioadhesive. The bioadhesive maybe distributed throughout the biocompatible matrix or only around theparticles containing the pharmaceutical agent (see discussion ofpharmaceutically active agent which may be incorporated into amicrosphere, liposomes, nanogels and other types of particle-based drugdelivery vehicles which are incorporated in the matrix, infra). Incertain embodiments, the bioadhesive adheres to the vessel or bodycavity wall. For example, the bioadhesive may comprise analginate-catechol mixture. Kastrup et al. PNAS 109: 21444-21449 (2012).In certain embodiments, the bioadhesive may comprise one or morehydrocolloid emulsifying agents. Non-limiting examples of hydrocolloidemulsifying agents that may be used include cellulosic emulsifyingagents and acrylic emulsifying agents, including, for example, thosewhich have an alkyl group containing from about 10 to about 50 carbonatoms. In certain embodiments, the acrylic emulsifying agents arecopolymers of a carboxylic acid and an acrylic ester (described, forexample, in U.S. Pat. Nos. 3,915,921 and 4,509,949), including thosewhich are cross-linked. An example of such cross-linked emulsifyingagent is “acrylates/C₁₀₋₃₀ alkyl acrylate crosspolymer”, a cross-linkedpolymer of acrylic acid and (₁₀₋₃₀) alkyl acrylates. Acrylates/C₁₀₋₃₀alkyl acrylate crosspolymer is available from Noveon, Inc. (previouslyB. F. Goodrich) and is sold under the trade name Pemulen®.Acrylates/C₁₀₋₃₀ alkyl acrylate crosspolymer has a small lipophilicportion and a large hydrophilic portion, thus allowing for it tofunction as a primary emulsifier for the formation of oil-in-wateremulsions. In addition, acrylates/C₁₀₋₃₀ alkyl acrylate crosspolymer iscapable of releasing the compounds of the dispersed phase upon contactwith a substrate, namely, biological membranes or mucosa and will notre-wet (the oil phase will not re-emulsify upon contact with water).Additional information regarding acrylates/C₁₀₋₃₀ alkyl acrylatecrosspolymer, which is listed in the U.S. Pharmacopeia, is provided inNoveon publications TDS-114, 117, 118, 124, 232-3, and 237, and PDSPemulen 1622.

Alkyl chain cyanoacrylates such as methyl-, ethyl-, isopropyl, butyl andoctylcyanoacrylate may be used as bioadhesives. U.S. Pat. No. 8,613,952;see also, Mizrahi et al. Acta Biomaterialia 7:3150-3157 (2011). Otherpossible bioadhesives include, but are not limited to, urethane-basedmaterials as well as adhesives incorporating mussel adhesive proteins.Mehdizadeh et al. Macromol Biosci. 13(3):271-288 (2013).

In certain embodiments, the bioadhesive can be prepared by combining:(i) a biopolymer having one or more first chemically reactive aminegroups; (ii) a biocompatible crosslinker having at least two secondchemically reactive groups that can chemically react with the one ormore first chemically reactive amine groups of the biopolymer; and (iii)a biocompatible rheological modifier. U.S. Patent Publication No.20160166728.

The biocompatible matrix may be mixed with a pharmaceutical acceptableexcipient, e.g., a carrier, adjuvant and/or diluent, according toconventional pharmaceutical compounding techniques. The excipients formodifying, maintaining or preserving, include, for example, the pH,osmolarity, viscosity, clarity, color, isotonicity, odor, sterility,stability, rate of dissolution or release, adsorption or penetration ofthe composition. Suitable excipients include, but are not limited to,amino acids (such as glycine, glutamine, asparagine, arginine orlysine); antimicrobials; antioxidants (such as ascorbic acid, sodiumsulfite or sodium hydrogen sulfite); buffers (such as borate,bicarbonate, Tris HC1, citrates, phosphates, other organic acids);bulking agents (such as mannitol or glycine), chelating agents (such asethylenediamine tetraacetic acid (EDTA), ethylene glycol tetraaceticacid (EGTA)); complexing agents (such as caffeine, polyvinylpyrrolidone,beta cyclodextrin or hydroxypropyl beta cyclodextrin); fillers;monosaccharides; disaccharides and other carbohydrates (such as glucose,mannose, or dextrins); proteins (such as serum albumin, gelatin orimmunoglobulins); coloring; flavoring and diluting agents; emulsifyingagents; hydrophilic polymers (such as polyvinylpyrrolidone); lowmolecular weight polypeptides; salt forming counterions (such assodium); preservatives (such as benzalkonium chloride, benzoic acid,salicylic acid, thimerosal, phenethyl alcohol, methylparaben,propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide);solvents (such as glycerin, propylene glycol or polyethylene glycol);sugar alcohols (such as mannitol or sorbitol); suspending agents;surfactants or wetting agents (such as pluronics, PEG, sorbitan esters,polysorbates such as polysorbate 20, polysorbate 80, triton,tromethamine, lecithin, cholesterol, tyloxapal);

stability enhancing agents (sucrose or sorbitol); tonicity enhancingagents (such as alkali metal halides (in one aspect, sodium or potassiumchloride, mannitol sorbitol); delivery vehicles; diluents; excipientsand/or pharmaceutical adjuvants. (Remington's Pharmaceutical Sciences,18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990).

The pharmaceutically active agent may be incorporated into amicrosphere, liposomes, nanogels and other types of particle-based drugdelivery vehicles which are incorporated in the biocompatible matrix.Hoare et al. Polymer 49:1993-2007 (2008). For example, Poly(lactic-co-glycolic acid) nanoparticles can be incorporated within across-linkable hyaluronan-based hydrogel matrix. Id.

Liposomes are microscopic lipid vesicles that are composed of a centralaqueous cavity surrounded by a lipid membrane formed by concentricbilayer(s) (lamellas). Liposomes are able to incorporate hydrophilicsubstances (in the aqueous interior) or hydrophobic substances (in thelipid membrane). Liposomes can be unilamellar vesicles (“UMV”), having asingle lipid bilayer, or multilamellar vesicles (“MLV”), having a seriesof lipid bilayers (also referred to as “oligolamellar vesicles”). Themultilamellar vesicles typically range in size from 0.2 μm to 10 μm indiameter. See e.g., WO 98/006882. The bilayer(s) of liposomes most oftencomprise phospholipids, but may also comprise lipids including, but notlimited to fatty acids, fatty acid salts and/or fatty alcohols. Theproperties of the liposomes depend, among other factors, on the natureof the constituents. Consequently, if liposomes with certaincharacteristics are to be obtained, the charge of its polar group and/orthe length and the degree of saturation of its fatty acid chains must betaken into account. In addition, the properties of liposomes may bemodified, e.g., to incorporate cholesterol and other lipids into themembrane, change the number of lipidic bilayers, or covalently joinnatural molecules (e.g., proteins, polysaccharides, glycolipids,antibodies, enzymes) or synthetic molecules (e.g., polyethyl glycol) tothe surface. There are numerous combinations of phospholipids,optionally with other lipids or cholesterol, in an aqueous medium thatcan be used to obtain liposomes. Depending on the method of preparationand the lipids used, it is possible to obtain vesicles of differentsizes, structures, and properties.

For example, the liposome can be formed from a homologous population ofa phospholipid, such as a neutral phospholipid, or a mixture ofdifferent types of phospholipids. Examples of phospholipid for makingthe delivery vehicle include, but are not limited to,phosphatidylcholine (PC), phosphatidylglycerol (PG),phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidicacid (PA), phosphatidylinositol (PI), egg phosphatidylcholine (EPC), eggphosphatidylglycerol (EPG), egg phosphatidylethanolamine (EPE), eggphosphatidylserine (EPS), egg phosphatidic acid (EPA), eggphosphatidylinositol (EPI), soy phosphatidylcholine (SPC), soyphosphatidylglycerol (SPG), soy phosphatidylethanolamine (SPE), soyphosphatidylserine (SPS), soy phosphatidic acid (SPA), soyphosphatidylinositol (SPI), dipalmitoylphosphatidylcholine (DPPC),1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC),dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylglycerol(DPPG), diolelphosphatidylglycerol (DOPG),dimyristoylphosphatidylglycerol (DMPG), hexadecylphosphocholine (HEPC),hydrogenated soy phosphatidylcholine (HSPC),distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol(DSPG), dioleylphosphatidylethanolamine (DOPE),palmitoylstearoylphosphatidylcholine (PSPC),palmitoylstearoylphosphatidylglycerol (PSPG),monooleoylphosphatidylethanolamine (MOPE),1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC),polyethyleneglycol distearoylphosphatidylethanolamine (PEG-DSPE),dipalmitoylphosphatidylserine (DPPS),1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS),dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine(DSPS), dipalmitoylphosphatidic acid (DPPA),1,2-dioleoyl-sn-glycero-3-phosphatidic acid (DOPA),dimyristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA),dipalmitoylphosphatidylinositol (DPPI),1,2-dioleoyl-sn-glycero-3-phosphatidylinositol (DOPI),dimyristoylphosphatidylinositol (DMPI), distearoylphosphatidylinositol(DSPI), and a mixture thereof.

Alternatively, the pharmaceutically active agent may be incorporatedinto a nanogel. Vinogradov et al. Expert Opin. Drug Deliv.4(1):5-17(2007). Nanogels are a polymer network of charged polyionicsegments cross-linked by polyethylene glycol (PEG) segments. U.S. Pat.No. 6,696,089. A wide variety of different pharmaceutically activeagents can be incorporated into the nanogel. Id.

The pharmaceutically active agent may be in the form of ananoparticulate suspension, a solid lipid nanoparticle, PLGAnanoparticles or LyoCells® can be incorporated into or encapsulated inthe biocompatible matrix. Hoare et al. Hydrogels in drug delivery:Progress and Challenges. Polymer 49:1993-2007 (2008).

The nanogel may be a nanoparticle composed of a crosslinked hydrophilicpolymer network (hydrogel). Nanogels are most often composed ofsynthetic polymers or biopolymers which are chemically or physicallycross-linked which are biocompatible. In yet another embodiment, thenanogels are biodegradable. Methods of obtaining nanogels are known inthe art as well as methods for obtaining nanogels that are biocompatibleand/or biodegradable (see U.S. Pat. No. 7,727,554). In one aspect, thenanogel comprises a linker that is biodegradable (e.g., wherein enzymes(e.g., physiological enzymes) can degrade the crosslinker, therebydegrading the nanogel). U.S. Patent Publication No. 20160250152.Nanogels (e.g., biodegradable nano gels) can be synthesized usingpolymers (e.g., N-isopropylacrylamide, N-vinyl pyrrolidone, pegylatedmaleic acid or a combination thereof) with a disulfide cross-linker.Nanogels formed using, for example, the above polymers may be about 50nm in diameter with sustained drug release properties. Nanogels may beformed from N-alkylacrylamide. In a particular aspect, theN-alkylacrylamide is poly-N-isopropylacrylamide. The nanogel can furthercomprises a vinyl monomer and a polyalkylene glycol. For example, thevinyl monomer can be vinyl pyrrolidone and the polyalkylene glycol canbe polyethylene glycol. The nanogel can further comprise sodiumacrylate. In particular aspects, the nanogel comprises about 500 toabout 1000 mg N-alkylacrylamide. In other aspect, the nanogel cancomprise about 100 to about 200 mg of the vinyl polymer and about 50 toabout 100 mg of the polyalkylene glycol. In yet other aspect, thenanogel comprises about 200 mg sodium acrylate. The size of the nanogelparticles may vary, ranging from a particle diameter of about 10 nm, 20nm, 40 nm, 60 nm, 80 nm, 100 nm, 120 nm, 140 nm, 160 nm, 180 nm, 200 nm,220 nm, 240 nm, 260 nm, 280 nm, 300 nm, 320 nm, 340 nm, 360 nm, 380 nm,400 nm, 420 nm, 440 nm, 460 nm, 480 nm, 500 nm, 520 nm, 540 nm, 560 nm,580 nm, 600 nm, 620 nm, 640 nm, 660 nm, 680 nm, 700 nm, 720 nm, 740 nm,760 nm, 780 nm, 800 nm, 820 nm, 840 nm, 860 nm, 880 nm, 900 nm, 920 nm,940 nm, 960 nm, 980 nm or about 1000 nm. In other aspect, the nanogelhas a zeta potential from about −10 mV, −15 mV, −20 mV, −25 mV, −30 mV,−35 mV, or −40 mV. The nanogel has a loading potential of about 2%, 3%,4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25% of the pharmaceuticallyuactive agent.

In certain embodiments, the pharmaceutically active agent can beencapsulated in a cyclodextrin particles containing cellulose ether witha particle size in the range of 50 to 1000 μm. Cyclodextrins areoligomers of anhydroglucose units, which are linked via alpha-1,4linkages into a ring shaped molecule. Depending upon the number of theunits one refers to these as alpha (6 unit), beta (7 unit) and gamma (8unit) cyclodextrin. These are conventionally produced from starch byenzymatic processes. The torroidal structure of the cyclodextrin makespossible the formation of an enclosing complex on a molecular level.

Pharmaceutically active agents that may be used in the present inventioninclude: (i) pharmacological agents such as, (a) anti-thrombotic agentssuch as heparin, heparin derivatives, urokinase, and PPack(dextrophenylalanine proline arginine chloromethylketone); (b)anti-inflammatory agents such as dexamethasone, prednisolone,corticosterone, budesonide, estrogen, sulfasalazine and mesalamine; (c)antineoplastic/antiproliferative/anti-miotic agents such as sirolimus(or its analogs, biolimus, everolimus or zotarolimus), paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin, angiopeptin, monoclonal antibodies capable ofblocking smooth muscle cell proliferation, thymidine kinase inhibitors,rapamycin, 40-0-(2-Hydroxyethyl)rapamycin (everolimus), 40-0-Benzyl-rapamycin, 40-0(4′-Hydroxymethyl)benzyl-rapamycin,40-0-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-Allyl-rapamycin,40-0-[3′-(2,2- Dimethyl-1,3-dioxolan-4(S)-yl-prop-2′-en-1′-yl]-20rapamycin, (2′:E,4′S)-40-0-(4′,5′.:Dihydroxypent-2′-en-1′ -yl),rapamycin 40-0(2Hydroxy) ethoxycar-bonylmethyl-rapamycin, 40-0-(3-Hydroxypropyl-rapamycin 40-0-((Hydroxy)hexyl-rapamycin40-0-[2(2-Hydroxy)ethoxy]ethyl-rapamycin,40-0-[(3S)-2,2Dimethyldioxolan-3-yl]methyl-rapamycin, 40-0-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-0-(2-Acctoxy)ethyl-rapamycin,40-0-(2-Nicotinoyloxy)ethyl-rapamycin, 40-0-[2-(N-25 Morpholino)acetoxyethyl-rapamycin, 40-0-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-0[2-(N-Methyl- N′-piperazinyeacetoxy]ethyl-rapamycin,39-0-Desmethyl-3.9,40-0,0 ethylene- rapamycin, (26R)-26-Dihydro-40-0-(2-hydroxy)ethyl-rapamycin, 28-O Methyrapamycin,40-0-(2-Aminoethyl)-rapamycin, 40-0-(2-Acetaminoethyl)-rapamycin40-0(2-Nicotinamidoethyl)-rapamycin, 40-0-(2-(N-Methyl- imidazo-2′ylcarbcthoxamido)ethyl)-30 rapamycin,40-0-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-0-(2-Tolylsulfonamidoethyl)-rapamycin,40-0-[2(4′,5′-Dicarboethoxy-1′,2′;3′-triazol-1′-yl)-ethyl]rapamycin,42-Epi-(telrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-24hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus) (WO2008/086369) (in various embodiments, the macrolideimmunosuppressive drug may be at least 50%, 75%, 90%, 98% or 99%crystalline; (d) anesthetic agents such as lidocaine, bupivacaine andropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethylketone, an RGD peptide-containing compound, heparin, hirudin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, prostaglandininhibitors, platelet inhibitors and tick antiplatelet peptides; (f)vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promotors; (g) vascular cell growthinhibitors such as growth factor inhibitors, growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors (e.g. , tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs;(j) cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobialagents such as triclosan, cephalosporins, aminoglycosides andnitrofurantoin; (m) cytotoxic agents, cytostatic agents and cellproliferation affectors; (n) vasodilating agents; and, (o) agents thatinterfere with endogenous vasoactive mechanisms, (ii) genetictherapeutic agents include anti-sense DNA and RNA as well as DNA codingfor (a) anti-sense RNA, (b) tRNA or rRNA to replace defective ordeficient endogenous molecules, (c) angiogenic factors including growthfactors such as acidic and basic fibroblast growth factors, vascularendothelial growth factor, epidermal growth factor, transforming growthfactor a and P, platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor a, hepatocytegrowth factor and insulin-like growth factor, (d) cell cycle inhibitorsincluding CD inhibitors, and (e) thymidine kinase (“TK”) and otheragents useful for interfering with cell proliferation.

Other pharmaceutically active agents that can be used, include,acarbosc, antigens, beta-receptor blockers, non-steroidalantiinflammatory drugs (NSAID;, cardiac glycosides, acetylsalicylicacid, virustatics, aclarubicin, acyclovir, cisplatin, actinomycin,alpha- and beta-sympatomimetics, (dmeprazole, allopurinol, alprostadil,prostaglandins, amantadine, ambroxol, amlodipine, methotrexate,S-aminosalicylic acid, amitriptyline, amoxicillin, anastrozole,atenolol, azathioprine, balsalazide, beclomcthasone, betahistine,bezafibrate, bicalutamide, diazepam and diazepam derivatives,budesonide, bufexamac, buprcnorphine, methadone, calcium salts,potassium salts, magnesium salts, candesartan, carbamazepine, captopril,cefalosporins, cetirizine, chenodeoxycholic acid, ursodeoxycholic acid,theophylline and theophylline derivatives, trypsins, cimetidine,clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidinc,cotrimoxazole, codeine, caffeine, vitamin D and derivatives of vitaminD, colestyramine, cromoglicic acid, coumarin and coumarin derivatives,cysteine, cytarabine, cyclophosphamide, cyclosporin, cyproterone,cytabarine, dapiprazole, desogestrel, desonide, dihydralazine,diltiazem, ergot alkaloids, dimenhydrinate, dimethyl sulphoxide,dimeticone, domperidone and domperidan derivatives, dopamine, doxazosin,doxorubizin, doxylamine, dapiprazole, benzodiazepines, diclofenac,glycoside antibiotics, desipramine, econazole, ACE inhibitors,enalapril, ephedrine, epinephrine, epoetin and epoetin derivatives,morphinans, calcium antagonists, irinotecan, modafmil, orlistat, peptideantibiotics, phenytoin, riluzoles, risedronate, sildenafil, topiramatc,macrolide antibiotics, oestrogen and oestrogen derivatives, progestogenand progestogen derivatives, testosterone and testosterone derivatives,androgen and androgen derivatives, ethenzamide, etofenamate, ctofibrate,fcnofibrate, etofylHne, etoposide, famciclovir, famotidine, felodipine,fenoftbrate, fentanyl, fenticonazole, gyrase inhibitors, fluconazole,fludarabine, fluarizine, fluorouracil, fluoxetine, flurbiprofen,ibuprofen, flutamide, fluvastatin, follitropin, formoterol, fosfomicin,furosemide, fusidic acid, gallopamil, ganciclovir, gemfibrozil,gentamicin, ginkgo, Saint John's wort, glibenclamide, urea derivativesas oral antidiabetics, glucagon, glucosamine and glucosaminederivatives, glutathione, glycerol and glycerol derivatives,hypothalamus hormones, goserelin, gyrase inhibitors, guanethidine,halofantrine, haloperidol, heparin and heparin derivatives, hyaluronicacid, hydralazine, hydrochlorothiazide and hydrochlorothiazidederivatives, salicylates, hydroxyzine, idarubicin, ifosfamide,imipramine, indometacin, indoramine, insulin, interferons, iodine andiodine derivatives, isoconazole, isoprenaline, glucitol and glucitolderivatives, itraconazole, ketoconazole, ketoprofen, ketotifen,lacidipine, lansoprazole, levodopa, levomethadone, thyroid hormones,lipoic acid and lipoic acid derivatives, lisinopril, lisuride,lofepramine, lomustine, loperamide, loratadine, maprotiline,mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine,meloxicam, mcpindolol, meprobamate, meropenem, mesalazinc, mesuximide,metamizole, metformin, methotrexate, methylphenidate,methylprednisolone, metixene, metoclopramide, metoprolol, metronidazole,mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin,mizolastinc, moexipril, morphine and morphine derivatives, eveningprimrose, nalbuphine, naloxone, tilidine, naproxen, narcotine,natamycin, neostigmine, nicergoline, nicethamide, nifedipine, niflumicacid, nimodipine, nimorazole, nimustine, nisoldipine, adrenaline andadrenaline derivatives, norfloxacin, novamine sulfone, noscapine,nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, omoconazole,ondansetron, oxaceprol, oxacillin, oxiconazole, oxymetazoline,pantoprazole, paracetamol, paroxetine, penciclovir, oral penicillins,pentazocine, pentifylline, pentoxifylline, perphenazine, pethidine,plant extracts, phenazone, pheniramine, barbituric acid derivatives,phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam,pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin,procaine, promazine, propiverine, propranolol, propyphenazone,prostaglandins, protionamide, proxyphylline, quetiapine, quinapril,quinaprilat, ramipril, ranitidine, reproterol, reserpine, ribavirin,rifampicin, risperidone, ritonavir, ropinirole, roxatidine,roxithromycin, ruscogenin, rutoside and rutoside derivatives, sabadilla,salbutamol, salmeterol, scopolamine, selegiline, sertaconazole,sertindole, sertralion, silicates, sildenafil, simvastatin, sitosterol,sotalol, spaglumic acid, sparfloxacin, spectinomycin, spiramycin,spirapril, spironolactone, stavudine, streptomycin, sucralfate,sufentanil, sulbactam, sulphonamides, sulfasalazine, sulpiride,sultamicillin, sultiam, sumatriptan, suxamethonium chloride, tacrine,tacrolimus, taliolol, tamoxifen, taurolidine, tazarotene, temazepam,teniposide, tenoxicam, terazosin, terbinafine, terbutaline, terfenadine,terlipressin, tertatolol, tctracyclins, teryzoline, theobromine,theophylline, butizine, thiamazole, phenothiazines, thiotepa, tiagabine,tiapride, propionic acid derivatives, ticlopidine, timolol, tinidazole,tioconazole, tioguanine, tioxolone, tiropramide, tizanidine, tolazolinc,tolbutamide, tolcapone, tolnaftate, tolperisone, topotecan, torasemide,antioestrogens, tramadol, tramazoline, trandolapril, tranylcypromine,trapidil, trazodone, triamcinolone and triamcinolone derivatives,triamterene, trifluperidol, trifluridine, trimethoprim, trimipramine,tripelennamine, triprolidine, trifosfamide, tromantadine, trometamol,tropalpin, troxerutine, tulobutcrol, tyramine, tyrothricin, urapidil,ursodeoxycholic acid, chenodeoxycholic acid, valaciclovir, valproicacid, vancomycin, vecuronium chloride, Viagra, venlafaxine, verapamil,vidarabine, vigabatrin, viloazine, vinblastine, vincamine, vincristine,vindesine, vinorclbinc, vinpocetine, viquidil, warfarin, xantinolnicotinate, xipamide, zafirlukast, zalcitabine, zidovudine,zolmitriptan, Zolpidem, zoplicone, zotipine and the like. See, e.g.,U.S. Pat. Nos. 6,897,205, 6,838,528 and 6,497,729.

In certain embodiments, mesenchymal stem cell particles, such asexosomes, may be incorporated into the biocompatible matrix or otherwisecoated on the balloon. U.S. Patent Publication No. 2015190430.Mesenchymal stem cell particles may be produced or from a mesenchymalstem cell (MSC). Such a method may comprise isolating the particle froma mesenchymal stem cell conditioned medium (MSC-CM). For example, themesenchymal stem cell particle may be isolated based on molecularweight, size, shape, composition or biological activity. The conditionedmedium may be filtered or concentrated or both during, prior to orsubsequent to separation and use. MSCs-derived exosomes may be used totreat cardiovascular disease, including, myocardial infarction,reperfusion injury and pulmonary hypertension. Huang et al. Exosomes inMesenchymal Stem Cells, a New Therapeutic Strategy for CardiovascularDiseases? Int J Biol Sci. 11(2):238-245 (2015).

Alternatively, a variety of DNA or RNA vectors may be incorporated intothe biocompatible matrix. For example, recombinant viruses includerecombinant adeno-associated virus (AAV), recombinant adenoviruses,recombinant lentiviruses, recombinant retroviruses, recombinantpoxviruses, and other known viruses in the art, as well as plasmids,cosmids, and phages may be used. Options for gene delivery viralconstructs are well known in the art (see, e.g., Ausubel et al., CurrentProtocols in Molecular Biology, John Wiley & Sons, New York, 1989; Kay,M. A., et al., 2001 Nat. Medic. 7(1):33-40; and Walther W. and Stein U.,2000 Drugs, 60(2): 249-71). Additionally, delivery vehicles such asnanoparticle- and lipid-based mRNA or protein delivery systems can beused as an alternative to AAV vectors. Further examples of alternativedelivery vehicles include lentiviral vectors, lipid-based deliverysystem, gene gun, hydrodynamic, electroporation or nucleofectionmicroinjection, and biolistics. Various gene delivery methods arediscussed in detail by Nayerossadat et al. (Adv Biomed Res. 2012; 1: 27)and Ibraheem et al. (Int J Pharm. 2014 Jan. 1; 459(1-2):70-83).

The present invention may be used with any balloon catheter stentdelivery system, including balloon catheter stent delivery systemsdescribed in U.S. Pat. Nos. 6,168,617, 6,222,097; 6,331,186; 6,478,814;7,169,162 or 20090254064.

The expandable cover may enclose the entire balloon or only a portion ofthe balloon. There exists an annular space or lumen between theexpandable cover and the balloon which may be sealed, i.e., not in fluidcommunication with the catheter or alternatively, may be in fluidcommunication with the catheter shaft. For example, the balloon cathetersystem can allow for the release of a fluid into the space or annularlumen between the balloon and the expandable cover. In this embodiment,the annular lumen or space is in communication with a fluid deliverylumen extending along the catheter shaft and the anular lumen or spacebetween the inflatable balloon and the expandable cover. Fluid passedthrough the fluid delivery lumen in the catheter shaft may be releasedinto the annular lumen or space hydrating the dehydrated biocompatiblematrix prior to or during insertion into the body cavity.

Balloon catheters such as those described in U.S. Patent Pub. No.20040006359 may also be used with the methods of the present invention.

The coating can be applied to a balloon either after the balloon hasbeen compacted for insertion or before insertion. The balloon iscompacted by, e.g., crimping or folding. U.S. Pat. Nos. 5,350,361,7,308,748 or 7,152,452. The balloon is delivered to the interventionsite by a delivery device such as a catheter. Balloons can be delivered,removed, and visualized during delivery and/or removal by methods wellknown in the art, see, e.g., U.S. Pat. Nos. 6,610,013 or 7,171,255. Theballoons of the present invention can include, compliant (expand, e.g.,16-40%, when pressurized), semi-compliant (expand, e.g., 7-16%, whenpressurized), and non-compliant balloons (expand, e.g., 2-7%, whenpressurized). The various characteristics, e.g., maximum distensions,i.e. distension from nominal diameter to burst, vary and are well knownin the art. Cutting balloons which are also used in angioplasty may beused with the methods and devices of the present invention. The balloonis inflated to a set inflation pressure which is determined by theoperator depending on the site and type of balloon. The “rated burstpressure” or “RBP” of the balloon is the maximum guaranteed pressure towhich a balloon can be inflated without failing.

The balloon may be coated with a lubricant coating before or afterapplication of the pharmaceutically active agent to reduce thecoefficient of friction between the pharmaceutically active agent orbiocompatible matrix and the balloon, i.e., sticking. The lubricantcoating may be a hydrophilic or hydrophobic coat. Examples of lubricantsto reduce the coefficient of friction used in medical devices include:silicone; colloidal solution of water and lecithin; polyphenyl ethers aselectrical connector lubricants; and the solid lubricants molybdenumdisulphide, PTFE or powdered graphite and boron nitride. The frictioncoefficients may be reduced as low as 0.001 or less. Alternatively,polymers having non-sticky surfaces can be produced by using a surfacemodifying compound such as Teflon®, fluoro-containing polymers andcopolymers, and the like with vinyl terminal or side groups for chemicalsolvent resistance and non-sticky surfaces. Polymers having hydrophilicsurfaces can be produced by using a surface modifying compound such aspolyvinylpyrrolidone, PVA, PEG, and the like. In addition, polymershaving a low surface friction can be produced by using a surfacemodifying compound such as polyvinylpyrrolidone, PVA, PEG, Teflon®, andthe like.

In one embodiment, the balloon 1.1 is positioned on a guidewire 1.2(FIG. 1). The guidewire 1.2 can have marker bands 1.3, 1.4 positioned ateither end of the balloon. The balloon can be in an expanded or inflated2.1 (FIG. 2), allowing release or extrusion of biocompatible matrix orhydrogel 2.2. After introduction into the blood vessel, the balloon maybe positioned adjacent to a atherosclerotic plaque. The balloon isintroduced into the blood vessel or body cavity in a folded or pleated(or uninflated) state prior to inflation, 3.1., 3.2, 3.3, 3.4 (guidewire3.5) (FIG. 3). The balloon is completely enclosed or enveloped in anexpandable cover 3.6. As the balloon inflates, the pleats unfold andafter full expansion, the balloon is completely unfolded (inflated). Inthe unexpanded state, the pleats of the balloon wrap around the body ofthe balloon which is positioned over the guidewire. The balloon maycontain 3, 4, 5, 6, 7, 8, 9, 10 . . . n pleats; the pleated size ratioto the inflated balloon can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 20 or 30.

After expansion, the slits or pores in the expandable cover enlarge 4.1(FIG. 4), allowing for extrusion of the biocompatible matrix into thebody cavity 4.2. This extrusion is shown in a closeup view as 5.1 (FIG.5). A cross section view of the balloon after expansion is shown in FIG.6. The balloon 6.1 surrounds the guidewire 6.2. The enlarged slits/poresare shown as 6.3. Through these slits or pores, the biocompatible matrix6.4 is extruded.

The biocompatible matrix can be formed from a spiral wrap 7.1 whichsurrounds, encloses or envelops the balloon 7.2 (FIG. 7). The wrappingwith the expandable cover 8.3 of the pleated balloon 8.2 is shown inFIG. 8. The matrix, 9.1, wrapped spirally around the balloon 9.2 isenclosed with a expandable cover 9.3 which contains slits/pores 9.4through which the matrix can be extruded (FIG. 9).

The subjects that can be treated using the medical device and methods ofthis invention are mammals, including, but not limited to, a human,horse, dog, cat, pig, rodent, monkey and the like.

The following are examples of the present invention and are not to beconstrued as limiting.

EXAMPLES Example 1 Balloon Coatings (Paclitaxel)

-   (a) 90% paclitaxel/10% Mpeg-PLGA in chloroform—Paclitaxel was mixed    in chloroform to a w/v concentration of 1.5% (15 mg/mL). The polymer    was mixed in chloroform to a w/v concentration of 1.5% (15 mg/mL).    The two solutions were then combined in the ratio of 90:10    respectively.-   (b) 90% paclitaxel/10% Mpeg-PDLA in chloroform—Paclitaxel was mixed    in chloroform to a w/v concentration of 1.5% (15 mg/mL). The polymer    was mixed in chloroform to a w/v concentration of 1.5% (15 mg/mL).    The two solutions were then combined in the ratio of 90:10    respectively.-   (c) 90% paclitaxel/10% Iohexol in Distilled (DI) Water—Paclitaxel    was mixed in acetone to a w/v concentration of 1.5% (15 mg/mL).    Iohexol was mixed in deionized water to a w/v concentration of 1.5%    (15 mg/mL). The two solutions were then combined in the ratios of    90:10 or 95:5 where applicable.-   (d) 90% paclitaxel/10% Urea in DI Water—Paclitaxel was mixed in    chloroform to a w/v concentration of 1.5% (15 mg/mL). The urea was    mixed in de-ionized water to a w/v concentration of 1.5% (15 mg/mL).    The two solutions were then combined in the ratio of 90:10    respectively.-   (e) Coating of Balloons—3.0 mm×15 mm Sapphire® balloons were coated    with the formulations listed above. Balloons were coated with target    doses were 1 μg/mm², 2 μg/mm² and 3 μg/mm². Coated balloons were    folded and sheathed immediately after coating.-   (f) Solubility Studies—Glass slides will be coated with the various    formulations. The coating will then be scraped off the glass slide    into a crucible. The coating will then be weighed on the analytical    balance (T/N 1160). Phosphate buffered saline (PBS) will be added to    the pre-weighed coating to make a 10 mg/mL solution. The solution    will then be vortexed for 3 minutes and filtered. 1 ml of solution    will be extracted and filtered into a test tube using a 3 mL syringe    and a 13 mm 0.45 μm PTFE filter. 1 ml of methanol will then be added    to the filtered PBS and “vortexed” for 20 secs in order to dissolve    any paclitaxel present. A lml sample will then b e analyzed for drug    (paclitaxel) content.

Example 2 Balloon Coatings (Sirolimus)

-   (a) 90% sirolimus/10% Mpeg-PLGA in chloroform—Sirolimus will be    mixed in chloroform to a w/v concentration of 1.5% (15 mg/mL). The    polymer will be mixed in chloroform to a w/v concentration of 1.5%    (15 mg/mL). The two solutions will then be combined in the ratio of    90:10 respectively.-   (b) 90% sirolimus/10% Mpeg-PDLA in chloroform—Sirolimus will be    mixed in chloroform to a w/v concentration of 1.5% (15 mg/mL). The    polymer will be mixed in chloroform to a w/v concentration of 1.5%    (15 mg/mL). The two solutions will then be combined in the ratio of    90:10 respectively.-   (c) 90% sirolimus/10% Iohexol in Distilled (DI) Water—Sirolimus will    be mixed in acetone to a w/v concentration of 1.5% (15 mg/mL).    Iohexol will be mixed in deionized water to a w/v concentration of    1.5% (15 mg/mL). The two solutions will then be combined in the    ratios of 90:10 or 95:5 where applicable.-   (d) 90% sirolimus/10% Urea in DI Water—Sirolimus will be mixed in    chloroform to a w/v concentration of 1.5% (15 mg/mL). The urea will    be mixed in de-ionized water to a w/v concentration of 1.5% (15    mg/mL). The two solutions will then be combined in the ratio of    90:10 respectively.-   (e) Coating of Balloons—3.0 mm×15 mm Sapphire® balloons will be    coated with the formulations listed above. Balloons will be coated    with target doses such as 1 μg/mm², 2 μg/mm² and 3 μg/mm². Coated    balloons will be folded and sheathed immediately with the expandable    cover after coating.-   (f) Solubility Studies—Glass slides will be coated with the various    formulations. The coating will then be scraped off the glass slide    into a crucible. The coating will then be weighed on the analytical    balance (T/N 1160). Phosphate buffered saline (PBS) will be added to    the pre-weighed coating to make a 10 mg/mL solution. The solution    will then be vortexed for 3 minutes and filtered. 1 ml of solution    will be extracted and filtered into a test tube using a 3 mL syringe    and a 13 mm 0.45 μm PTFE filter. 1 ml of methanol will be then added    to the filtered PBS and vortexed for 20 secs in order to dissolve    any sirolimus present. A 1 ml sample will then be analyzed for drug    (sirolimus) content.

Example 3 Elution Profile

-   (a) Elution Profile Kinetics—The coated balloon, with and without    the expandable cover, will be placed in different 1 ml aliquots of    PBS at 37° C. for a series of defined times, e.g., 30 seconds, 1, 2,    3, 4, 5, 10, 15, 30, 60 and 120 minutes in order to generate an    elution profile over time. Aliquots of PBS will then be analyzed by    high pressure liquid chromatography (HPLC) to establish sirolimus    concentrations in solution at each time point. Calibration standards    containing known amounts of sirolimus will be used to determine the    amount of sirolimus eluted. The multiple peaks present for sirolimus    (also present in the calibration standards) will be added to give    the amount of sirolimus eluted at that time period (in absolute    amount and as a cumulative amount eluted). High pressure liquid    chromatography (HPLC) analysis will then performed using Waters HPLC    system.

Example 4 Clinical Simulation Test

-   (a) In-Vitro Mass Loss Test: The coated balloon with the expandable    cover, prepared as in Example 2, will be weighed on a microbalance    and then secured to a balloon catheter. A segment of optically clear    TYGON® tubing will be filled with phosphate buffered saline (PBS)    and immersed in a water bath at 37° C. in order to to mimic    physiological conditions of deployment in the body cavity of a    subject. The coated balloon will be inserted into the tubing and the    balloon will be inflated to at least about 25% to about 70% below    the balloon's rated burst pressure (e.g., 5-15 atm) for 30 seconds,    1, 2, 3, 4, 5, 10, 15, 30, 60 or 120 minutes. The balloon will be    deflated and then removed from the tubing. After drying, the balloon    will be further dried and weighed on a microbalance. A comparison of    the pre- and post-deployment weights indicates how much coating is    freed, dissociated, and/or transferred from the balloon.-   (b) In-Vitro Testing for Distal Flow: The coated balloon, prepared    in Example 2, will be secured to a guidewire incorporating a porous    filter of 100 μm pore size. A segment of TYGON® tubing will be    filled with PBS and immersed in a water bath at 37° C. The coated    balloon enclosed with the expandable cover will be inserted into the    tubing. The flow of PBS through the TYGON tubing will be started,    the distal filter will be deployed and the balloon will be inflated    to at least 25% to about 70% below the balloon's rated burst    pressure (e.g., 5-15 atm) for 30 seconds, 1, 2, 3, 4, 5, 10, 15, 30,    60 or 120 minutes. The balloon will be deflated and removed from the    tubing. The filter will be deployed for 5 minutes after removal of    the balloon and the flow of PBS will be halted, the tubing cut    adjacent to the epoxy seal, the filter retracted and removed from    the tubing. The content of the filter will be analyzed for the    presence of sirolimus containing particles.

Example 5 Expanding Coated Balloon in Yucatan Minswine Arteries

A coated balloon will be prepared and then secured to a ballooncatheter. Briefly, a balloon will be dip-coated in a coating composition(e.g., described in Example 1 or Example 2). The balloon will then bedried, folded, and secured to a balloon catheter.

A segment of resected coronary artery from Yucatan miniature swine willbe positionally fixed and filled with PBS. The coronary artery will thenbe immersed in a water bath at 37° C. in order to mimic physiologicalconditions of deployment in a subject. The coated balloon will beinserted into the tubing and the balloon will be inflated to at leastabout 25% to about 70% below the balloon's rated burst pressure (e.g.,5-15 atm) for 30 seconds, 1, 2, 3, 4, 5, 10, 15, 30, 60 or 120 minutes.The balloon will be deflated and removed from the artery. The section ofartery exposed to the deployed balloon will be cut away from theremainder of the artery section, placed into a tissue homogenizer andthe homogenized material extracted with methylene chloride to make up 25mL total volume of rinsings which will be collected in a flask foranalysis. Analysis by HPLC as described above will be performed todetermine the amount of sirolimus transferred from the balloon throughthe expandable cover to the coronary artery at each time point.

Sirolimus will also be extracted from the balloon by placing it in a 5mL glass test tube containing 1 mL of methanol and vortexing forapproximately 20 seconds. The balloon will be removed from the test tubeand the contents of the test tube will be filtered into a 1 mLautosampler vial using a 3 mL syringe and 0.45 micron filter. Sirolimusconcentrations will be assayed by HPLC.

Example 6 Optical Microscopy and Scanning Electron Microscopy (SEM) ofthe Balloon and Coating

A coated balloon will be prepared using a coating composition, e.g.,described in Example 1 or Example 2. The balloon will be covered with anexpandable cover and immersed in PBS at 37° C. The coated balloon willbe inserted into the TYGON® tubing as described above and the balloonwill be inflated to at least about 25% to about 70% below the balloon'srated burst pressure (e.g., 5-15 atm) for about 30 seconds, 1, 2, 3, 4,5, 10, 15, 30, 60 or 120 minutes. The balloon will be deflated andremoved from the TYGON® tubing. SEM and Optical microscopy will beperformed on the balloon and the expandable cover to determine physicalchanges occurred to the surfaces of the balloon and the expandable coverassociated with transfer, disassociation, and displacement of thecoating.

Example 7 In Vivo Analysis of Active Pharmaceutical Agent at Site ofApplication

A group of 10 New Zealand white rabbits will beprepared for a Seldingerprocedure using a balloon coated with a formulation of sirolimus withtotal loading of sirolimus of approximately, 20-60 μg. The coatedballoon will then enclosed by the expandable cover and then placed inthe coronary artery. The covered and coated balloon catheter will bepositioned with the assistance of fluoroscopy. Six animals will besubjected to the procedure using a coated balloon that does not havesirolimus in the coating. After deployment and removal of the balloon, 2control animalswill be sacrificed at 1 hour post deployment and serumand tissue samples will be collected. The 3 remaining control animalswill be sacrificed at 56 days post deployment. During the course of thestudy, serum samples will be collected from control and drug-treatedanimals every five days. The drug treated animals, 3 each, will besacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42 days and 56days post-deployment. The tissue and serum samples will be subjected toanalysis for sirolimus concentration by HPLC as described above.

Example 8

The balloon is wrapped with a tape formed from Pullulan. Pullulan is apolysaccharide polymer consisting of maltotriose units, also known asα-1,4-;α-1,6-glucan (see,https://pubchem.ncbi.nlm.nih.gov/compound/92024139, retrieved Jun. 30,2017). The Pullulan may be mixed with an active pharmaceuticalingredient (API). The API may be suspended directly in the Pullulan.Alternatively, the API may be suspended in a particles such as: (i)Nanoparticulate suspensions; (ii) Solid lipid nanoparticles; (iii) PLGA;or (iv) LyoCells® (see,http://www.particlesciences.com/docs/technical_briefs/TB_2012_4-Cubic-Phase-Particles-in-Drug-Delivery.pdf,retrieved Jun. 30, 2017). These examples of partciles is non-limiting.

Only a portion of the balloon may be wrapped. As shown below, thePullulan tape wraps the distal segment of the balloon (distal to thehandle). Alternatively, the Pullulan tape wraps the proximal segment ofthe balloon (proximal to the handle). The balloon may be wrapped 1, 2,3, 4, 5, 6, 7, 8, 9, 10 . . . n times with the Pullulan tape. Theballoon may be wrapped with two or more (2, 3, 4, 5, 6, 7, 8, 9, 10 . .. n) different Pullulan tapes containing different APIs as well asdifferent particles for suspension of the API. Various configurations ofthe wrapping are shown below.

FIGS. 10A-10G illustrate the following possible configurations whichshould be considered non-limiting.

FIG. 10A. The balloon is shown with the tape wrapped around the proximalportion of the balloon.

FIG. 10B. The balloon is shown with the tape wrapped around the distalportion of the balloon.

FIG. 10C. The balloon is shown with four (4) wraps of the tape aroundthe balloon.

FIG. 10D. The balloon is shown with two different tapes, Tape 1 and Tape2, wrapped around the balloon.

FIG. 10E. The balloon is shown with two different tapes, Tape 1 and Tape2, wrapped around the proximal, Tape 1, and distal, Tape 2, portions ofthe balloon.

FIG. 10F. The Pullulan is shown with two different APIs, APi₁ and API₂,suspended in a nanoparticle, API₁ and a liposome, API₂.

FIG. 10G. The balloon is shown with four different Tapes, Tapes 1-4,aligned longitudinally along the balloon.

The scope of the present invention is not limited by what has beenspecifically shown and described hereinabove. Those skilled in the artwill recognize that there are suitable alternatives to the depictedexamples of materials, configurations, constructions and dimensions.Numerous references, including patents and various publications, arecited and discussed in the description of this invention. The citationand discussion of such references is provided merely to clarify thedescription of the present invention and is not an admission that anyreference is prior art to the invention described herein. All referencescited and discussed in this specification are incorporated herein byreference in their entirety. Variations, modifications and otherimplementations of what is described herein will occur to those ofordinary skill in the art without departing from the spirit and scope ofthe invention. While certain embodiments of the present invention havebeen shown and described, it will be obvious to those skilled in the artthat changes and modifications may be made without departing from thespirit and scope of the invention. The matter set forth in the foregoingdescription and accompanying drawings is offered by way of illustrationonly and not as a limitation.

1-30. (canceled)
 31. A medical device, comprising a balloon, a lubricantcoating, a biocompatible matrix and an expandable polymer cover, whereinthe lubricant coating is coated on the balloon before application of thebiocompatible matrix, the biocompatible matrix is disposed between theballoon and the expandable polymer cover, wherein the biocompatiblematrix is a thin film having a thickness ranging from 3μm to about 250μm, the biocompatible matrix comprising a bioabsorbable polymer, a firstlayer comprising microspheres, liposomes, nanoparticles, cyclodextrin ormixtures thereof, a second layer comprising microspheres, liposomes,nanoparticles, cyclodextrin or mixtures and a macrolide drug, whereinthe macrolide drug is released into an aqueous environment for at least25 days after the balloon is inflated.
 32. The medical device of claim31, wherein the biocompatible matrix comprises shellac andpolyvinylpyrollidone, ethyl cellulose hydroxypropylmethyl cellulose,dextran, alginate, amylose, amylopectin, carrageenan, carboxymethylcellulose, gellan, guar gum, polysaccharide conjugate vaccines,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose, amylopectin, starch derivatives,hyaluronic acid, starch derivatives, xantan, xyloglucan, chitosan-basedhydrogel, peptidoglycan, and proteoglycans, glucose, maltose, lactose,fructose, sucrose, galactose, glucosamine, galactosamine, muramic acid,glucruronate, gluconate, fucose, trehalose, a synthetic polymer, such aspolyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, propyleneglycol, polyoxyethylene derivatives, a polypeptide, such as elastin,polyvinyl amine or poly(L-lysine), carboxymethyl cellulose (CMC),hydroxypropylmethyl cellulose (HPMC), amylopectin, starch derivatives,hyaluronic acid, pullulan, poly(lactide-co-glycolide), polylactic acid,polyglycolic acid, polyanhydride, polycaprolactone, polyhydroxybutyratevalerate, or copolymers thereof, collagen, fibronectin, vitronectin,elastin, laminin, heparin, fibrin, cellulose, carbon,poly(lactide-co-glycolide); poly-DL-lactide, poly-L-lactide, ethylenevinyl acetate (EVAC), polybutyl-methacrylate (PBMA) andmethylmethacrylate (MMA), pullulan or mixtures thereof.
 33. The medicaldevice of claim 31, wherein the biocompatible matrix comprises,aliphatic polyesters, bioglass cellulose, chitin collagen copolymers ofglycolide, copolymers of lactide, elastin, tropoelastin, fibrin,glycolide/1-lactide copolymers (PGA/PLLA), glycolide/trimethylenecarbonate copolymers (PGA/TMC), hydrogel lactide/tetramethylglycolidecopolymers, lactide/trimethylene carbonate copolymers,lactide/-ε-caprolactone copolymers, lactide-σ-valerolactone copolymers,L-lactide/d1-lactide copolymers, methyl methacrylate-N-vinyl pyrrolidonecopolymers, modified proteins, nylon-2 PHBA/γ-hydroxyvalerate copolymers(PHBA/HVA), PLA/polyethylene oxide copolymers, PLA-polyethylene oxide(PELA), poly (amino acids), poly (trimethylene carbonates), polyhydroxyalkanoate polymers (PHA), poly(alklyene oxalates), polybutylenediglycolate), poly(hydroxy butyrate) (PHB), poly(n-vinyl pyrrolidone),poly(ortho esters), polyalkyl-2-cyanoacrylates, polyanhydrides,polycyanoacrylates, polydepsipeptides, polydihydropyrans,poly-d1-lactide (PDLLA), polyesteramides, polyesters of oxalic acid,polyglycolide (PGA), polyiminocarbonates, polylactides (PLA),polyorthoesters, poly-p-dioxanone (PDO), polypeptides, polyphosphazenes,polysaccharides, polyurethanes (PU), polyvinyl alcohol (PVA),poly-β-hydroxypropionate (PHPA), poly-β-hydroxybutyrate (PBA),poly-α-valerolactone, poly-β-alkanoic acids, poly-β-malic acid (PMLA),poly-ε-caprolactone (PCL), pseudo-Poly(Amino Acids), starch,trimethylene carbonate (TMC) and tyrosine based polymers or mixturesthereof.
 34. The medical device of claim 32, wherein the biocompatiblematrix comprises pullulan.